Lactobacillus delbrueckii alleviates lipopolysaccharide-induced muscle inflammation and atrophy in weaned piglets associated with inhibition of endoplasmic reticulum stress and protein degradation.

Pro-inflammatory cytokines in muscle play a pivotal role in physiological responses and in the pathophysiology of inflammatory disease and muscle atrophy. Lactobacillus delbrueckii (LD), as a kind of probiotics, has inhibitory effects on pro-inflammatory cytokines associated with various inflammatory diseases. This study was conducted to explore the effect of dietary LD on the lipopolysaccharide (LPS)-induced muscle inflammation and atrophy in piglets and to elucidate the underlying mechanism. A total of 36 weaned piglets (Duroc × Landrace × Large Yorkshire) were allotted into three groups with six replicates (pens) of two piglets: (1) Nonchallenged control; (2) LPS-challenged (LPS); (3) 0.2% LD diet and LPS-challenged (LD+LPS). On d 29, the piglets were injected intraperitoneally with LPS or sterilized saline, respectively. All piglets were slaughtered at 4 h after LPS or saline injection, the blood and muscle samples were collected for further analysis. Our results showed that dietary supplementation of LD significantly attenuated LPS-induced production of pro-inflammatory cytokines IL-6 and TNF-α in both serum and muscle of the piglets. Concomitantly, pretreating the piglets with LD also clearly inhibited LPS-induced nuclear translocation of NF-κB p65 subunits in the muscle, which correlated with the anti-inflammatory effects of LD on the muscle of piglets. Meanwhile, LPS-induced muscle atrophy, indicated by a higher expression of muscle atrophy F-box, muscle RING finger protein (MuRF1), forkhead box O 1, and autophagy-related protein 5 (ATG5) at the transcriptional level, whereas pretreatment with LD led to inhibition of these upregulations, particularly genes for MuRF1 and ATG5. Moreover, LPS-induced mRNA expression of endoplasmic reticulum stress markers, such as eukaryotic translational initiation factor 2α (eIF-2α) was suppressed by pretreatment with LD, which was accompanied by a decrease in the protein expression levels of IRE1α and GRP78. Additionally, LD significantly prevented muscle cell apoptotic death induced by LPS. Taken together, our data indicate that the anti-inflammatory effect of LD supply on muscle atrophy of piglets could be likely regulated by inhibiting the secretion of pro-inflammatory cytokines through the inactivation of the ER stress/NF-κB singling pathway, along with the reduction in protein degradation.

20(S)-ginsenoside Rg3 protects against diabetic muscle atrophy by promoting myoblastic differentiation and protecting mitochondrial function.

BACKGROUND: High glucose levels are a primary cause of diabetes-associated cellular dysfunction and tissue damage. Muscles are the key insulin target organ and therefore, have a high level of sensitivity to hyperglycemia. Our previous study revealed that 20(S)-ginsenoside Rg3 (S-Rg3) is a monomer with a good myogenic differentiation effect in ginsenoside. Furthermore, it can alleviate dexamethasone-induced muscle atrophy by protecting mitochondrial function. However, whether S-Rg3 is effective for diabetic-induced muscle atrophy has not been reported. PURPOSE: This study aimed to investigate the protective effect of S-Rg3 on diabetic-induced muscle atrophy. METHODS: C2C12 myoblasts, Drosophila, and mice were used as model systems, and the protective effect of S-Rg3 on diabetes was evaluated by assessing the levels of glucose and lipids. Furthermore, H&E, toluidine blue, Giemsa, and immunofluorescence staining were performed to detect the effects of S-Rg3 on muscle atrophy and myogenic differentiation. Moreover, the effects of S-Rg3 on mitochondrial morphology and function were also evaluated by electron microscopy, flow cytometry, and Seahorse. In addition, the underlying pathways of S-Rg3 effects were detected by Western blot. The related inhibitors and gene mutations in Drosophila were used for validation. RESULTS: The analysis of diabetic mice model fed with a high-fat diet (HFD) and high glucose (HG) revealed that in the injured C2C12 myoblasts, S-Rg3 treatment significantly reduced the levels of triglycerides and glucose. Furthermore, it promoted the differentiation of myoblasts and inhibited mitochondrial dysfunction. In the Drosophila HG and HFD diabetic model, S-Rg3 reduced triglyceride and trehalose levels, increased climbing distance values, promoted myoblasts differentiation, preserved mitochondrial function, and inhibited muscle atrophy. Mechanistically, the beneficial effects of S-Rg3 were at least partially associated with the phosphorylation of AMPK and FoxO3 together with the inhibition of Smad3 phosphorylation, this pathway was validated by the UAS-AMPKα-RNAi Drosophila model. CONCLUSION: In summary, this study revealed mechanistic insights into how S-Rg3 protects against diabetes-associated muscle atrophy in cells, Drosophila, and mice.

The role of ZEB1 in mediating the protective effects of metformin on skeletal muscle atrophy.

Metformin is an important antidiabetic drug that has the potential to reduce skeletal muscle atrophy and promote the differentiation of muscle cells. However, the exact molecular mechanism underlying these functions remains unclear. Previous studies revealed that the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1), which participates in tumor progression, inhibits muscle atrophy. Therefore, we hypothesized that the protective effect of metformin might be related to ZEB1. We investigated the positive effect of metformin on IL-1ß-induced skeletal muscle atrophy by regulating ZEB1 in vitro and in vivo. Compared with the normal cell differentiation group, the metformin-treated group presented increased myotube diameters and reduced expression levels of atrophy-marker proteins. Moreover, muscle cell differentiation was hindered, when we artificially interfered with ZEB1 expression in mouse skeletal myoblast (C2C12) cells via ZEB1-specific small interfering RNA (si-ZEB1). In response to inflammatory stimulation, metformin treatment increased the expression levels of ZEB1 and three differentiation proteins, MHC, MyoD, and myogenin, whereas si-ZEB1 partially counteracted these effects. Moreover, marked atrophy was induced in a mouse model via the administration of lipopolysaccharide (LPS) to the skeletal muscles of the lower limbs. Over a 4-week period of intragastric administration, metformin treatment ameliorated muscle atrophy and increased the expression levels of ZEB1. Metformin treatment partially alleviated muscle atrophy and stimulated differentiation. Overall, our findings may provide a better understanding of the mechanism underlying the effects of metformin treatment on skeletal muscle atrophy and suggest the potential of metformin as a therapeutic drug.

Vigeo Promotes Myotube Differentiation and Protects Dexamethasone-Induced Skeletal Muscle Atrophy via Regulating the Protein Degradation, AKT/mTOR, and AMPK/Sirt-1/PGC1α Signaling Pathway In Vitro and In Vivo.

Sarcopenia, a condition caused by an imbalance between muscle growth and loss, can severely affect the quality of life of elderly patients with metabolic, inflammatory, and cancer diseases. Vigeo, a nuruk-fermented extract of three plants (Eleutherococcus senticosus Maxim (ESM), Achyranthes japonica (Miq.) Nakai (AJN), and Atractylodes japonica Koidzumi (AJK)) has been reported to have anti-osteoporotic effects. However, evidence of the effects of Vigeo on muscle atrophy is not available. Here, in the in vivo model of dexamethasone (Dex)-induced muscle atrophy, Vigeo treatment significantly reversed Dex-induced decreases in calf muscle volume, gastrocnemius (GA) muscle weight, and histological cross-section area. In addition, in mRNA and protein analyses isolated from GA muscle, we observed that Vigeo significantly protected against Dex-induced mouse muscle atrophy by inhibiting protein degradation regulated by atrogin and MuRF-1. Moreover, we demonstrated that Vigeo significantly promoted C2C12 cell line differentiation, as evidenced by the increased width and length of myotubes, and the increased number of fused myotubes with three or more nuclei. Vigeo alleviated the formation of myotubes compared to the control group. Vigeo also significantly increased the mRNA and protein expression of myosin heavy chain (MyHC), MyoD, and myogenin compared to that in the control. Vigeo treatment significantly reduced the mRNA and protein expression of muscle degradation markers atrogin-1 and muscle RING Finger 1 (MuRF-1) in the C2C12 cell line in vitro. Vigeo also activated the AMP-activated protein kinase (AMPK)/silent information regulator 1 (Sirt-1)/peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) mitochondrial biogenesis pathway and the Akt/mTOR protein synthesis signaling pathway in Dex-induced myotube atrophy. These findings suggest that Vigeo may have protective effects against Dex-induced muscle atrophy. Therefore, we propose Vigeo as a supplement or potential therapeutic agent to prevent or treat sarcopenia accompanied by muscle atrophy and degeneration.

Pharmacological activation of pyruvate dehydrogenase by dichloroacetate protects against obesity-induced muscle atrophy in vitro and in vivo.

Obesity-induced muscle atrophy leads to physical impairment and metabolic dysfunction, which are risky for older adults. The activity of pyruvate dehydrogenase (PDH), a critical regulator of glucose metabolism, is reduced in obesity. Additionally, PDH activator dichloroacetate (DCA) improves metabolic dysfunction. However, the effects of PDH activation on skeletal muscles in obesity remain unclear. Thus, this study aimed to evaluate the effects of PDH activation by DCA treatment on obesity-induced muscle atrophy in vitro and in vivo and elucidate the possible underlying mechanisms. Results showed that PDH activation by DCA treatment ameliorated muscle loss, decreased the cross-sectional area, and reduced grip strength in C57BL/6 mice fed a high-fat diet (HFD). Elevation of muscle atrophic factors atrogin-1 and muscle RING-finger protein-1 (MuRF-1) and autophagy factors LC3BII and p62 were abrogated by DCA treatment in palmitate-treated C2C12 myotubes and in the skeletal muscles of HFD-fed mice. Moreover, p-Akt, p-FoxO1, and p-FoxO3 protein levels were reduced and p-NF-κB p65 and p-p38 MAPK protein levels were elevated in palmitate-treated C2C12 myotubes, which were restored by DCA treatment. However, the protective effects of DCA treatment against myotube atrophy were reversed by treatment with Akt inhibitor MK2206. Taken together, our study demonstrated that PDH activation by DCA treatment can alleviate obesity-induced muscle atrophy. It may serve as a basis for developing novel strategies to prevent obesity-associated muscle loss.

Effects of Rehabilitative Exercise and Neuromuscular Electrical Stimulation on Muscle Morphology and Dynamic Balance in Individuals with Chronic Ankle Instability.

Background and Objectives: Muscle atrophy caused by chronic ankle instability (CAI) can incur muscle weakness, altered movement patterns, and increased risk of injury. Previous studies have investigated the effects of rehabilitative exercises and neuromuscular electrical stimulation (NMES) on characteristics in CAI individuals, but few studies have examined their effects on foot and ankle muscle morphology. This study aimed to determine the effects of rehabilitative exercises and NMES on muscle morphology and dynamic balance in individuals with CAI. Materials and Methods: Participants with CAI (n = 47) were randomly divided into control (CG), rehabilitative exercise (REG), NMES (NG), and rehabilitative exercise and NMES combined (RNG) groups. The six-week intervention program consisting of rehabilitative exercises and NMES was applied to groups excluding CG. Muscle morphology and dynamic balance were evaluated using a portable wireless diagnostic ultrasound device and dynamic balance tests. For statistical analysis, an effect size with 95% confidence interval was calculated to assess mean differences according to intervention. Results: After six weeks, significant increases in morphology and dynamic balance were observed for all muscles except flexor hallucis longus (p > 0.05) in the intervention groups except for CG. However, no significant changes were observed in the CG (p > 0.05). Conclusions: These findings suggest that intervention programs may help prevent muscle atrophy and improve balance in CAI individuals.

Exercise Attenuate Diaphragm Atrophy in COPD Mice via Inhibiting the RhoA/ROCK Signaling.

Background: Exercise is an indispensable component of pulmonary rehabilitation with strong anti-inflammatory effects. However, the mechanisms by which exercise prevents diaphragmatic atrophy in COPD (chronic obstructive pulmonary disease) remain unclear. Methods: Forty male C57BL/6 mice were assigned to the control (n=16) and smoke (n=24) groups. Mice in the smoke group were exposed to the cigarette smoke (CS) for six months. They were then divided into model and exercise training groups for 2 months. Histological changes were observed in lung and diaphragms. Subsequently, agonist U46639 and antagonist Y27632 of RhoA/ROCK were subjected to mechanical stretching in LPS-treated C2C12 myoblasts. The expression levels of Atrogin-1, MuRF-1, MyoD, Myf5, IL-1ß, TNF-α, and RhoA/ROCK were determined by Western blotting. Results: Diaphragmatic atrophy and increased RhoA/ROCK expression were observed in COPD mice. Exercise training attenuated diaphragmatic atrophy, decreased the expression of MuRF-1, and increased MyoD expression in COPD diaphragms. Exercise also affects the upregulation of RhoA/ROCK and inflammation-related proteins. In in vitro experiments with C2C12 myoblasts, LPS remarkably increased the level of inflammation and protein degradation, whereas Y27632 or combined with mechanical stretching prevented this phenomenon considerably. Conclusion: RhoA/ROCK plays an important role in the prevention of diaphragmatic atrophy in COPD.

Dihydromyricetin Inhibits Ferroptosis to Attenuate Cisplatin-Induced Muscle Atrophy.

Cisplatin is a widely used chemotherapy drug for the treatment of various cancers. However, although cisplatin is effective in targeting cancer cells, it has severe side effects including skeletal muscle atrophy. In this study, we aimed to characterize the role of Dihydromyricetin in cisplatin-induced muscle atrophy in mice. 5-week-old male C57BL/6 mice were treated with Dihydromyricetin for 14 days orally followed by in intraperitoneally cisplatin administration for 6 days. Gastrocnemius muscles were isolated for the following experiments. Antioxidative stress were determined by peroxidative product malondialdehyde (MDA) and antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Quadriceps muscle mass and grip strength were significantly restored by Dihydromyricetin in a dose-dependent manner. Moreover, muscle fibers were improved in Dihydromyricetin treated group. Excessive skeletal muscle E3 ubiquitin-protein ligases in cisplatin group were significantly repressed by Dihydromyricetin treatment. Dihydromyricetin significantly reduced oxidative stress induced by cisplatin by decreasing MDA level and restored SOD and GPx activities. In addition, ferroptosis was significantly reduced by Dihydromyricetin characterized by reduced iron level and ferritin heavy chain 1 and improved Gpx4 level. The present study demonstrated that Dihydromyricetin attenuated cisplatin-induced muscle atrophy by reducing skeletal muscle E3 ubiquitin-protein ligases, oxidative stress, and ferroptosis.

Perioperative Glutamine Supplementation May Restore Atrophy of Psoas Muscles in Gastric Adenocarcinoma Patients Undergoing Gastrectomy.

BACKGROUND: Sarcopenia, characterized by degenerative skeletal muscle loss, is increasingly linked to poor surgical outcomes. Glutamine, an immune-modulating formula, may stimulate muscle protein synthesis and inhibit degradation. We used the psoas major muscle area (PMMA) at the third lumbar vertebra, normalized for height (PMMA index), as a skeletal muscle indicator. This study investigates whether perioperative glutamine supplementation mitigates psoas muscle atrophy. METHODS: We enrolled gastric adenocarcinoma (GA) patients undergoing gastrectomy. Computed tomography assessed the psoas muscle short axis. Muscle atrophy was estimated by changes between preoperative and three-month post-gastrectomy scans. Perioperative glutamine supplementation (PGS) comprised five-day parenteral plus one-month oral use. Propensity score matching minimized potential bias. A linear regression model predicted the association. RESULTS: Of 516 patients analyzed (2016-2019), 100 (19.4%) received PGS. After propensity score matching, each group contained 97 cases. The PGS group showed a significantly higher median PMMA index change than the non-PGS group (0.3 vs. -0.3 cm2/m2, p = 0.004). Multivariate analysis revealed that PGS was significantly associated with increased PMMA index (coefficient = 0.60; 95% CI: 0.19-1.01; p = 0.005). CONCLUSIONS: PGS may help restore psoas muscle atrophy in GA patients undergoing gastrectomy. The underlying mechanisms likely relate to glutamine's role in protein metabolism and immune function. Further studies are needed to elucidate these mechanisms fully.

Muscle-Protective Effect of Carnosine against Dexamethasone-Induced Muscle Atrophy in C2C12 Myotube.

This study investigated the protective effect of carnosine and its components (L-histidine and ß-alanine [HA]) against dexamethasone (Dex)-induced muscle atrophy in C2C12 myotubes. Myotubes were treated with Dex (10 µM) to induce muscle atrophy manifested by decreased myotube diameter, low myosin heavy chain content, and increased expression of muscle atrophy-associated ubiquitin ligases (Atrogin-1, MuRF-1, and Cbl-b). Carnosine (20 mM) treatment significantly improved the myotube diameter and MyHC protein expression level in Dex-treated C2C12 myotubes. It also downregulated the expression of Atrogin-1, MuRF-1, and Cbl-b and suppressed the expression of forkhead box O3 (FoxO3a) mediated by Dex. Furthermore, reactive oxygen species production was increased by Dex but was ameliorated by carnosine treatment. However, HA (20 mM), the component of carnosine, treatment was found ineffective in preventing Dex-induced protein damage. Therefore, based on above results it can be suggested that carnosine could be a potential therapeutic agent to prevent Dex-induced muscle atrophy compared to its components HA.

Blood flow restriction Exercise in the perioperative setting to Prevent loss of muscle mass in patients with pancreatic, biliary tract, and liver cancer: study protocol for the PREV-Ex randomized controlled trial.

BACKGROUND: Patients diagnosed with pancreatic, biliary tract, and liver cancer often suffer from a progressive loss of muscle mass. Given the considerable functional impairments in these patients, high musculoskeletal weight loads may not be well tolerated by all individuals. The use of blood-flow restricted resistance training (BFR-T) which only requires low training loads may allow for a faster recovery of muscle due to avoidance of high levels of mechanical muscle stress associated with high-load resistance exercise. This study aims to investigate whether BFR-T can prevent or slow down the loss of skeletal muscle mass and enhance the functional capacity and mental health of patients with pancreatic, biliary tract, and liver cancer. METHODS: The PREV-Ex exercise trial is a multicenter two-armed randomized controlled trial. Patients will be randomized to an exercise program consisting of home-based low-load BFR-T during a combined pre- and postoperative period for a total of 6-10 weeks (prehabilitation and rehabilitation), or to a control group. Protein supplementation will be given to both groups to ensure adequate protein intake. The primary outcomes, skeletal muscle thickness and muscle cross-sectional area, will be assessed by ultrasound. Secondary outcomes include the following: (i) muscle catabolism-related and inflammatory bio-markers (molecular characteristics will be assessed from a vastus lateralis biopsy and blood samples will be obtained from a sub-sample of patients); (ii) patient-reported outcome measures (self-reported fatigue, health-related quality of life, and nutritional status will be assessed through validated questionnaires); (iii) physical fitness/performance/activity (validated tests will be used to evaluate physical function, cardiorespiratory fitness and maximal isometric muscle strength. Physical activity and sedentary behavior (assessed using an activity monitor); (iv) clinical outcomes: hospitalization rates and blood status will be recorded from the patients' medical records; (v) explorative outcomes of patients' experience of the exercise program which will be evaluated using focus group/individual interviews. DISCUSSION: It is worthwhile to investigate new strategies that have the potential to counteract the deterioration of skeletal muscle mass, muscle function, strength, and physical function, all of which have debilitating consequences for patients with pancreatic, biliary tract, and liver cancer. The expected findings could improve prognosis, help patients stay independent for longer, and possibly reduce treatment-related costs. TRIAL REGISTRATION: ClinicalTrials.gov NCT05044065. Registered on September 14, 2021.

Exercise following joint distraction inhibits muscle wasting and delays the progression of post-traumatic osteoarthritis in rabbits by activating PGC-1α in skeletal muscle.

OBJECTIVE: Muscle wasting frequently occurs following joint trauma. Previous research has demonstrated that joint distraction in combination with treadmill exercise (TRE) can mitigate intra-articular inflammation and cartilage damage, consequently delaying the advancement of post-traumatic osteoarthritis (PTOA). However, the precise mechanism underlying this phenomenon remains unclear. Hence, the purpose of this study was to examine whether the mechanism by which TRE following joint distraction delays the progression of PTOA involves the activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as its impact on muscle wasting. METHODS: Quadriceps samples were collected from patients with osteoarthritis (OA) and normal patients with distal femoral fractures, and the expression of PGC-1α was measured. The hinged external fixator was implanted in the rabbit PTOA model. One week after surgery, a PGC-1α agonist or inhibitor was administered for 4 weeks prior to TRE. Western blot analysis was performed to detect the expression of PGC-1α and Muscle atrophy gene 1 (Atrogin-1). We employed the enzyme-linked immunosorbent assay (ELISA) technique to examine pro-inflammatory factors. Additionally, we utilized quantitative real-time polymerase chain reaction (qRT-PCR) to analyze genes associated with cartilage regeneration. Synovial inflammation and cartilage damage were evaluated through hematoxylin-eosin staining. Furthermore, we employed Masson's trichrome staining and Alcian blue staining to analyze cartilage damage. RESULTS: The decreased expression of PGC-1α in skeletal muscle in patients with OA is correlated with the severity of OA. In the rabbit PTOA model, TRE following joint distraction inhibited the expressions of muscle wasting genes, including Atrogin-1 and muscle ring finger 1 (MuRF1), as well as inflammatory factors such as interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in skeletal muscle, potentially through the activation of PGC-1α. Concurrently, the production of IL-1ß, IL-6, TNF-α, nitric oxide (NO), and malondialdehyde (MDA) in the synovial fluid was down-regulated, while the expression of type II collagen (Col2a1), Aggrecan (AGN), SRY-box 9 (SOX9) in the cartilage, and superoxide dismutase (SOD) in the synovial fluid was up-regulated. Additionally, histological staining results demonstrated that TRE after joint distraction reduced cartilage degeneration, leading to a significant decrease in OARSI scores.TRE following joint distraction could activate PGC-1α, inhibit Atrogin-1 expression in skeletal muscle, and reduce C-telopeptides of type II collagen (CTX-II) in the blood compared to joint distraction alone. CONCLUSION: Following joint distraction, TRE might promote the activation of PGC-1α in skeletal muscle during PTOA progression to exert anti-inflammatory effects in skeletal muscle and joint cavity, thereby inhibiting muscle wasting and promoting cartilage regeneration, making it a potential therapeutic intervention for treating PTOA.

Oleocanthal Protects C2C12 Myotubes against the Pro-Catabolic and Anti-Myogenic Action of Stimuli Able to Induce Muscle Wasting In Vivo.

Oleocanthal (OC) is a monophenol of extra-virgin olive oil (EVOO) endowed with antibiotic, cardioprotective and anticancer effects, among others, mainly in view of its antioxidant and anti-inflammatory properties. OC has been largely investigated in terms of its anticancer activity, in Alzheimer disease and in collagen-induced arthritis; however, the possibility that it can also affect muscle biology has been totally overlooked so far. This study is the first to describe that OC modulates alterations induced in C2C12 myotubes by stimuli known to induce muscle wasting in vivo, namely TNF-α, or in the medium conditioned by the C26 cachexia-inducing tumor (CM-C26). C2C12 myotubes were exposed to CM-C26 or TNF-α in the presence or absence of OC for 24 and 48 h and analyzed by immunofluorescence and Western blotting. In combination with TNF-α or CM-C26, OC was revealed to be able to restore both the myotube's original size and morphology and normal levels of both atrogin-1 and MuRF1. OC seems unable to impinge on the autophagic-lysosomal proteolytic system or protein synthesis. Modulations towards normal levels of the expression of molecules involved in myogenesis, such as Pax7, myogenin and MyHC, were also observed in the myotube cultures exposed to OC and TNF-α or CM-C26. In conclusion, the data presented here show that OC exerts a protective action in C2C12 myotubes exposed to TNF-α or CM-C26, with mechanisms likely involving the downregulation of ubiquitin-proteasome-dependent proteolysis and the partial relief of myogenic differentiation impairment.

Epigallocatechin gallate protects against fat and muscle atrophy in B16BL6 melanoma-bearing mice on a high-fat diet.

AIMS: Epidemiological evidence indicates that there is a substantial association between body mass index (BMI) and at least ten forms of cancer, including melanoma, and BMI imbalance contributes to the poor survival rate of cancer patients before and after therapy. Nevertheless, few pharmacological studies on models of obesity and cancer have been reported. In this study, we administered epigallocatechin gallate (EGCG) to B16BL6 tumor-bearing mice that received a high-fat diet (HFD) to examine its impact. METHODS: B16BL6 tumor-bearing mice were fed a HFD. Body weight and food intake were documented every week. We conducted a Western blot analysis to examine the protein levels in the tumor, gastrocnemius (GAS), and tibialis anterior (TA) muscles, as well as the inguinal and epididymal white adipose tissues (iWAT and eWAT). KEY FINDINGS: EGCG has been shown to have anti-cancer effects equivalent to those of cisplatin, a chemotherapy drug. Furthermore, EGCG protected against the loss of epidydimal white adipose tissue by regulating protein levels of lipolysis factors of adipose triglyceride lipase and hormone-sensitive lipase as well as WAT browning factors of uncoupling protein 1, as opposed to cisplatin. EGCG was shown to reduce the protein levels of muscular atrophy factors of muscle RING-finger protein-1, whereas cisplatin did not contribute to rescuing the atrophy of TA and GAS muscles. CONCLUSION: Taken together, our findings indicate that EGCG has a preventive effect against cachexia symptoms and has anti-cancer effects similar to those of cisplatin in tumor-bearing mice fed a high-fat diet.

Reversal of Soleus Muscle Atrophy in Older Adults: A Non-Volitional Exercise Intervention for a Changing Climate.

The World Health Organization recommends that older adults undertake at least 150 minutes of moderate intensity physical activity over the course of each week in order to maintain physical, mental, and social health. This goal turns out to be very difficult for most community dwelling older adults to achieve, due to both actual and perceived barriers. These barriers include personal health limitations, confinement issues, and self-imposed restrictions such as fear of injury. Climate change exacerbates the confinement issues and injury fears among the elderly. To assist older adults in obtaining the benefits of increased physical activity under increasingly challenging climate conditions, we propose a targeted non-volitional intervention which could serve as a complement to volitional physical activity. Exogenous neuro-muscular stimulation of the soleus muscles is a non-invasive intervention capable of significantly increasing cardiac output in sedentary individuals. Long-term daily use has been shown to improve sleep, reduce bone loss, and reverse age-related cognitive decline, all of which are significant health concerns for older adults. These outcomes support the potential benefit of exogenous neuro-muscular stimulation as a complementary form of physical activity which older adults may find convenient to incorporate into their daily life when traditional forms of exercise are difficult to achieve due to barriers to completing traditional physical activities as a result of in-home or in-bed confinement, perceptual risks, or real environmental risks such as those arising from climate change.

Sea Cucumber-Inspired Microneedle Nerve Guidance Conduit for Synergistically Inhibiting Muscle Atrophy and Promoting Nerve Regeneration.

Muscle atrophy resulting from peripheral nerve injury (PNI) poses a threat to a patient's mobility and sensitivity. However, an effective method to inhibit muscle atrophy following PNI remains elusive. Drawing inspiration from the sea cucumber, we have integrated microneedles (MNs) and microchannel technology into nerve guidance conduits (NGCs) to develop bionic microneedle NGCs (MNGCs) that emulate the structure and piezoelectric function of sea cucumbers. Morphologically, MNGCs feature an outer surface with outward-pointing needle tips capable of applying electrical stimulation to denervated muscles. Simultaneously, the interior contains microchannels designed to guide the migration of Schwann cells (SCs). Physiologically, the incorporation of conductive reduced graphene oxide and piezoelectric zinc oxide nanoparticles into the polycaprolactone scaffold enhances conductivity and piezoelectric properties, facilitating SCs' migration, myelin regeneration, axon growth, and the restoration of neuromuscular function. These combined effects ultimately lead to the inhibition of muscle atrophy and the restoration of nerve function. Consequently, the concept of the synergistic effect of inhibiting muscle atrophy and promoting nerve regeneration has the capacity to transform the traditional approach to PNI repair and find broad applications in PNI repair.

Nutritional Strategies for Muscle Atrophy: Current Evidence and Underlying Mechanisms.

Skeletal muscle can undergo detrimental changes in various diseases, leading to muscle dysfunction and atrophy, thus severely affecting people's lives. Along with exercise, there is a growing interest in the potential of nutritional support against muscle atrophy. This review provides a brief overview of the molecular mechanisms driving skeletal muscle atrophy and summarizes recent advances in nutritional interventions for preventing and treating muscle atrophy. The nutritional supplements include amino acids and their derivatives (such as leucine, ß-hydroxy, ß-methylbutyrate, and creatine), various antioxidant supplements (like Coenzyme Q10 and mitoquinone, resveratrol, curcumin, quercetin, Omega 3 fatty acids), minerals (such as magnesium and selenium), and vitamins (such as vitamin B, vitamin C, vitamin D, and vitamin E), as well as probiotics and prebiotics (like Lactobacillus, Bifidobacterium, and 1-kestose). Furthermore, the study discusses the impact of a combined approach involving nutritional support and physical therapy to prevent muscle atrophy, suggests appropriate multi-nutritional and multi-modal interventions based on individual conditions to optimize treatment outcomes, and enhances the recovery of muscle function for patients. By understanding the molecular mechanisms behind skeletal muscle atrophy and implementing appropriate interventions, it is possible to enhance the recovery of muscle function and improve patients' quality of life.

Combination of Parenteral Amino Acid Infusion and Intermittent Loading Exercise Ameliorates Progression of Postoperative Sarcopenia in Rat Model.

Postoperative sarcopenia is associated with poor outcomes in hospitalized patients. However, few studies have focused on short-term postoperative sarcopenia. Furthermore, the influence of nutritional management using amino acids (AAs) comprising a peripheral parenteral nutrition (PPN) solution and its combination with exercise (Exc) is unclear. Hence, we established a postoperative sarcopenic rat model to evaluate the effects of parenteral AA infusion combined with Exc on skeletal muscles and investigate the underlying mechanisms involved in the amelioration of muscle atrophy. Male F344 rats underwent surgery followed by hindlimb suspension (HS) for 5 days. The rats were divided into AA (-), AA (+), AA (-)-Exc, and AA (+)-Exc groups. They were continuously administered a PPN solution with or without AA at 98 kcal/kg/day. The Exc groups were subjected to intermittent loading for 1 h per day. Postoperative sarcopenic rats exhibited decreased muscle strength and mass and an upregulated ubiquitin-proteasome system, autophagy-lysosome system, and fast-twitch fiber-related genes, especially in the AA (-) group. The AA (+)-Exc group exhibited attenuated decreased muscle strength, increased gastrocnemius mass, and a suppressed upregulation of muscle atrophy- and fast-twitch fiber-related genes. Therefore, parenteral AA infusion combined with Exc may be effective in preventing postoperative sarcopenia in hospitalized patients.

IL-33-ST2 signaling in fibro-adipogenic progenitors alleviates immobilization-induced muscle atrophy in mice.

BACKGROUND: The regenerative and adaptive capacity of skeletal muscles reduces with age, leading to severe disability and frailty in the elderly. Therefore, development of effective therapeutic interventions for muscle wasting is important both medically and socioeconomically. In the present study, we aimed to elucidate the potential contribution of fibro-adipogenic progenitors (FAPs), which are mesenchymal stem cells in skeletal muscles, to immobilization-induced muscle atrophy. METHODS: Young (2-3 months), adult (12-14 months), and aged (20-22 months) mice were used for analysis. Muscle atrophy was induced by immobilizing the hind limbs with a steel wire. FAPs were isolated from the hind limbs on days 0, 3, and 14 after immobilization for transcriptome analysis. The expression of ST2 and IL-33 in FAPs was evaluated by flow cytometry and immunostaining, respectively. To examine the role of IL-33-ST2 signaling in vivo, we intraperitoneally administered recombinant IL-33 or soluble ST2 (sST2) twice a week throughout the 2-week immobilization period. After 2-week immobilization, the tibialis anterior muscles were harvested and the cross-sectional area of muscle fibers was evaluated. RESULTS: The number of FAPs increased with the progression of muscle atrophy after immobilization in all age-groups. Transcriptome analysis of FAPs collected before and after immobilization revealed that Il33 and Il1rl1 transcripts, which encode the IL-33 receptor ST2, were transiently induced in young mice and, to a lesser extent, in aged mice. The number of FAPs positive for ST2 increased after immobilization in young mice. The number of ST2-positive FAPs also increased after immobilization in aged mice, but the difference from the baseline was not statistically significant. Immunostaining for IL-33 in the muscle sections revealed a significant increase in the number of FAPs expressing IL-33 after immobilization. Administration of recombinant IL-33 suppressed immobilization-induced muscle atrophy in aged mice but not in young mice. CONCLUSIONS: Our data reveal a previously unknown protective role of IL-33-ST2 signaling against immobilization-induced muscle atrophy in FAPs and suggest that IL-33-ST2 signaling is a potential new therapeutic target for alleviating disuse muscle atrophy, particularly in older adults.

Caffeic acid alleviates skeletal muscle atrophy in 5/6 nephrectomy rats through the TLR4/MYD88/NF-kB pathway.

Skeletal muscle atrophy is a common complication of chronic kidney disease (CKD) that affects the quality of life and prognosis of patients. We aimed to investigate the effects and mechanisms of caffeic acid (CA), a natural phenolic compound, on skeletal muscle atrophy in CKD rats. Male Sprague-Dawley rats underwent 5/6 nephrectomy (NPM) and were treated with CA (20, 40, or 80 mg/kg/day) for 10 weeks. The body and muscle weights, renal function, hemoglobin, and albumin were measured. The histological, molecular, and biochemical changes in skeletal muscles were evaluated using hematoxylin-eosin staining, quantitative real-time PCR, malondialdehyde/catalase/superoxide dismutase/glutathione level detection, and enzyme-linked immunosorbent assay. Western blotting and network pharmacology were applied to identify the potential targets and pathways of CA, CKD, and muscle atrophy. The results showed that CA significantly improved NPM-induced muscle-catabolic effects, reduced the expression of muscle atrophy-related proteins (muscle atrophy F-box and muscle RING finger 1) and proinflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-alpha, and IL-1ß), and attenuated muscle oxidative stress. Network pharmacology revealed that CA modulated the response to oxidative stress and nuclear factor kappa B (NF-κB) signaling pathway and that Toll-like receptor 4 (TLR4) was a key target. In vivo experiment confirmed that CA inhibited the TLR4/myeloid differentiation primary response 88 (MYD88)/NF-kB signaling pathway, reduced muscle iron levels, and restored glutathione peroxidase 4 activity, thereby alleviating ferroptosis and inflammation in skeletal muscles. Thus, CA might be a promising therapeutic agent for preventing and treating skeletal muscle atrophy in CKD by modulating the TLR4/MYD88/NF-κB pathway and ferroptosis.